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Transcript
Acute and chronic inflammation. Repair: cell growth and regeneration. Wound healing. 2011 Acute inflammation is early, immediate, response of vascularized living tissue to local injury, non-specific its purpose is 1) to destroy injurious agent 2) to reconstitute a damaged tissue (healing) repair already begins during early phases of inflammation injured tissue is replaced by regeneration of parenchymal cells by connective tissue formation - scarring Causes of inflammation microbial infections: bacteria, viruses, fungi, etc. hypersensitivity reactions physical agents: burns, UV light, radiation, trauma chemical agents: acids, alkalis, oxidising agents, toxins, endotoxins, even toxic catabolites derived from endogenous processes, such as in uraemia, etc. tissue necrosis: ischemia Main clinical signs and symptoms of inflammation Acute inflammation is characterised by five major signs described by Celsus and Virchow rubor = redness from dilatation of blood vessels calor = increased heat and fever- redness and heat due to an increased rate and volume of blood flow because of vasodilatation, release of pyrogens tumor = swelling from edema dolor = pain form oedema and histamine release, pain is said to be due to an accumulation of acid metabolites that stimulate nerve endings functio laesa = loss of function form pain and swelling Morphologic and functional changes in acute inflammation microcirculatory response cellular response CELLS OF THE INFLAMMATORY RESPONSE Neutrophilic leukocytes Eosinophilic leukocytes leukocytes are the first cells to appear at the site of acute inflammation is to degrade cell debris and to ingest and kill microbesphagocytosis associated with hypersensitivity responses Basophils and mast cells mast cells are usually seen in tissues in type I hypersensitivity reactions mediated by IgE binding of IgE to the receptor on mast cells and basophils leads to degranulation of granules and release of the granule contents (heparin, histamine, and enzymes, such as acid hydrolase) into the tissues Monocytes and macrophages macrophages are major scavenger cells of the body enzymes, such as lysozyme and hydrogen peroxide- degrade particulate material including micro-organisms they control many of the cellular, vascular and reparative responses of inflammation by releasing chemotactic factors, cytokines (tumour necrosis factor) and growth factors (PDGF) and transforming growth factor beta (TGF-beta) Lymphocytes and plasma cells these are principal cells of specific immune responses- produce antibodies Microcirculatory response increased blood flow and permeability of blood vessels Vasodilatation leads to hyperaemia (= increased amount of blood in infl. area )- heat and redness increased permeability of blood vessels- associated with slowing of the circulation- called stasis increased passage of fluid out of microcirculation because of increased permeability in acute inflammation = exudation of fluid vascular leakage- loss of protein-rich fluid from blood vessels reduction of osmotic pressure within blood vessels increase in interstitium- accumulation of fluid out of blood vessels inflammatory oedema- major feature of acute inflammation Formation of transudate and exudate The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation (2) extravasation of plasma fluid and proteins (edema) (3) leukocyte emigration Composition of inflammatory exudate exudate is fluid rich in plasma proteins (albumins, immunoglobulins, fibrinogen) converted into fibrin by tissue tromboplastin Fibrin can be recognised microscopically-pink fibres or clumps, macroscopically- most easily seen on acute infl. of serosal surfaces-acute fibrinous pericarditis- „bread and butter„ appearance. Transudation= increased passage of fluids (very low level of plasma proteins, and no cells) through blood vessels with normal permeability- increased hydrostatic pressure or decreased plasma osmotic pressure composition similar to ultrafiltrate of plasma Significance of the process of exudation Exudation helps to destroy infectious agent by its diluting by flooding the area with blood rich in immunoglobulins and other important defensive proteins by increasing lymphatic flow -lymphatic drainage may to spread infectious agents acute inflammation of lymphatics= lymphangitis acute inflammation of lymph nodes= lymphadenitis Cellular response NEUTROPHILIC LEUKOCYTES MACROPHAGES LYMPHOCYTES remain predominant cell type for several days in acute inflammation. emigration of neutrophils -leukocytes actively leave the blood vessel by moving through dilated intercellular junctions, pass through basement membrane and reach the extracellular space movements of these cells are similar to that of neutrophils- chemotactic mediators for macrophages- complement factor C5 and lymphokines (secreted by lymphocytes) ERYTHROCYTES enter extracellular space passively – RBCs are pushed out from the blood vessel by hydrostatic pressure- the process is called erythrodiapedesis when large numbers of erythrocytes enter the inflamed area = haemorrhagic inflammation Major events in phagocytosis recognition and attachment of bacteria by the phagocytic cells - either directly (large inactive particles) or after opsonization (antigen is coated by opsonins) engulfment - extensions of cytoplasm (pseudopods) flow around the particles - formation of phagocytic vacuole, this vacuole fuses with membrane of lysosomal vacuolesdegranulation of leukocytes bacterial killing and degradation-killing of bacterial organisms is accomplished by activities of reactive oxygen species Failure of oxidative metabolism during phagocytosis leads to a severe disorder of immunity = in chronic granulomatous disease of childhood Phagocytosis of a particle (e.g., a bacterium) involves: MORPHOLOGIC PATTERNS IN ACUTE INFLAMMATION Serous inflammation is characterised by abundant serous exudate derived either from the blood stream or from the secretory activity of mesothelial cells pleural or pericardial cavities, skin, mucosal surfaces serous exudate is easily removed- complete regeneration Acute inflammation Serous Serous inflammation Fibrinous inflammation Caused by more serious injuries permeability of blood vessel is greater and more proteins including large molecules of fibrinogen pass the vascular wall Fibrinous exsudate can be removed-process called resolution when fibrinous exsudate is not removed fibrin may stimulate the ingrowth of fibroblasts into the blood vessel wall, thus leading to scarring- this process is called organization Acute inflammation Fibrinous Fibrinous inflammation Suppurative or purulent inflammation is characterized by production of large amounts of purulent exsudate (pus) Abscess localized collection of purulent exudate Ulcer = is a local defect in the tissue, mainly in the mucosal or cutaneous surfaces Acute inflammation Purulent (suppurative) Purulent-suppurative inflammation Bronchopneumonia Purulent inflammation Acute inflammation Purulent (suppurative) peritonitis Ulcerative, pseudomembranous inflammation acute ulcer- intense leukocyte infiltrate and vascular dilatation in the margins chronic ulcer -more developed fibroblastic reaction, scarring and infiltration of lymphocytes, macrophages and plasma cells Fibrinopurulent and pseudomebranous Pseudomembranous colitis SYSTEMIC CLINICAL SIGNS OF ACUTE INFLAMMATION fever changes in the peripheral white blood cells leucocytosis- the total number of neutrophils in the peripheral blood is increased is common feature especially in bacterial infections „ shift to the left“ means an increased number of immature neutrophils in peripheral blood Leukocyte count-may reach levels of about 15 or 20 thousands cells per mm3- extreme levels (more than 40 thousand)- referred to as leukemoid reaction viral infections tend to produce neutropenia (decreased number of leukocytes) with lymphocytosis (excess of lymphocytes in the blood) results either of direct activity of cytokines or through local activity of prostaglandins CHRONIC INFLAMMATION acute inflammation usually disappears after a few days and tissue returns to normal Complete resolution -means total restoration and regeneration of Healing by scarring -occurs after tissue destruction, in case of Progression to chronic inflammation injured area. tissue defects, with abundant fibrin leakage, secondary infection, chronic inflammatory response may follow acute inflammation that failed to destroy injurious agent or may be chronic from the onset (without a clinically apparent acute phase) Outcomes of acute inflammation: resolution, healing by scarring, or chronic inflammation Causes of chronic inflammation persistent infection - caused by distinctive infectious agents, such as mycobacterium, treponema pallidum, some fungi, by organisms of lower toxicity, by intracellular organisms prolonged exposure to undegradable material, such as silica particles, carbon particles which, after being inhaled, set up a chronic inflammatory response in lungs autoimmune diseases= immune reaction set up against own tissues or cells - reveal a chronic inflammatory pattern- for example rheumatoid arthritis MORPHOLOGIC FEATURES AND CLINICAL SIGNS OF CHRONIC INFLAMMATION chronic inflammation is an inflammatory response it is distinguished from acute inflammation characterized by the presence of lymphocytes, plasma cells and macrophages by the absence of cardinal signs such as rubor, calor, dolor, tumor active hyperemia, fluid exudation and neutrophilic emigration are absent it is distinguished from acute inflammation by its long duration, which permits a manifestation of immune response Often associated with scarring, fibroproliferation chronic acute Histologic hallmarks of chronic inflammation infiltration by macrophages, lymphocytes and plasma cells proliferation of fibroblasts and myofibroblasts and proliferation of small blood vessels, together known as formation of granulation tissue in most cases, the process of chronic inflammation is accompanied by a proliferation of connective tissue (deposition of collagen fibres), referred to as fibrosis usually marked tissue destruction Granulation tissue Reparation component of inflammation is represented by granulation tissue composed of budding capillaries, fibroblasts and occasional inflammatory cells CHRONIC INFLAMMATORY CELLS MACROPHAGES play central role in chronic inflammatory infiltrate-macrophages are the most effective phagocytic cells in acute and chronic inflammatory response enzymatic degradation and phagocytic activity following activation-macrophages produce biologically active products, such as: enzymes - neutral and acid proteases chemotactic factors for leukocytes growth factors and promoting factors for fibroblasts and blood vessels- thus macrophages may modulate a formation of nonspecific granulation tissue cytokines, such as interleukin I , TNF,etc. PLASMA CELLS produce antibodies directed against persistent antigens or against altered tissue components LYMPHOCYTES when activated by the contact with antigen, lymphocytes release lymphokines- many of them stimulate macrophages on the other hand, lymphocytes may be stimulated by cytokines released by activated macrophages EOSINOPHILS are characteristic of immunologic reaction mediated by IgE and of parasitic infections NEUTROPHILIC LEUKOCYTES in chronic inflammation of bone marrow (osteomyelitis)- large numbers of neutrophils may persists for months also chronic inflammation of fallopian tube may have the pattern of chronic suppuration with large numbers of neutrophils FIBROBLASTS fibroproduction and accumulation of extracellular proteins- characteristic features of chronic inflammatory response MORPHOLOGIC TYPES OF CHRONIC INFLAMMATORY RESPONSE GRANULOMATOUS CHRONIC INFLAMMATION is characterized by formation of epithelioid granulomas granuloma- is defined as an aggregate of macrophages, two types of granulomas are recognised epithelioid granuloma- represents immune response macrophages are activated by T-lymphocytes „ epithelioid cell“ are activated macrophages - large cells with abundant pale foamy cytoplasm - superficial resemblance to epithelial cells typical feature of epithelioid granulomas is formation of Langhans-type giant cells- are derived from macrophages Chronic granulomatous inflammation Langhans cell Epithelioid histiocytes Granuloma (also called „specific granulation tissue“) is composed of modified macrophages) Epithelioid granulomas occur in infection due to intracellular organisms Tuberculosis (Mycobacterium Tuberculosis) Leprosy (Mycobacterium leprae) Syphilis (Treponema pallidum) Cat-scratch disease (Gram negative bacillus)-rounded or stellate granulomas usually within lymph nodes containing the central granular debris and leukocytes Several parasitic and fungal infections (schistosomiasis, cryptococcus) Sarcoidosis (Mycobacterium) disorders due to chemical agents such as beryllium (berylliosis) Crohn disease Tuberculosis Tuberculosis is characterized by specific granulomas, caseous necrosis and finding of Mycobacterium tuberculosis (Ziehl-Nielsen stain) Chronic granulomatous inflammation Sarcoidosis ?allergic reaction to the presence of non-virulent mycobacteria? Chronic granulomatous inflammation Sarcoidosis Asteroid inclusions Schaumann´s inclusions Granuloma without caseous necrosis Hamazaki – Wesenberg inclusions NONGRANULOMATOUS CHRONIC INFLAMMATION accumulation of sensitised lymphocytes, plasma cells and macrophages chronic viral infections in chronic autoimmune diseases persistent infection of parenchymal cells by viruses evokes an immune response- the affected tissue shows presence of lymphocytes and plasmacytes, cytotoxic effect is mediated either by killer- T-lymphocytes or by cytotoxic antibodies immune response is also mediated by killer- T-lymphocytes or by cytotoxic antibodies the antigen is a host cell molecule which is recognised as foreign by immune system pathologic result is cell necrosis, resulting in fibrosis and lymphocytic and plasmacytic infiltration in chronic inflammation due to chemical toxic substances alcohol produces chronic inflammation – liver, pancreas cell necrosis - alteration in host molecule - becomes antigenic and evoke immune response REPAIR. CELL GROWTH AND REGENERATION. WOUND HEALING resolution -removal of debris associated with a complete restoration of the tissue to preinjury state regeneration - complete replacement of necrotic parenchymal cells by new parenchymal cells of the same quality resolution and regeneration- ideal outcome of healing- is possible only in the tissues with prevailing labile cells (cells capable of mitotic division- complete regeneration) if complete resolution and regeneration is not possible, necrotic foci may be replaced by collagen this process is termed organisation repair by scar formation REGENERATION replacement of lost parenchymal cells is dependent on regenerative capacity of the cells number of surviving cells maintenance of basement membranes or presence of stem cell layer The cells of the body can be divided into 3 groups on the basis of their regenerative capacity and their relation to the cell cycle: Labile cell (intermitotic) Stable cell (reversible postmitotic ) Permanent cell (irreversible postmitotic) Labile cells continuously dividing cells- they continue to proliferate, remain all the time in cell cycle Healing in tissues with many labile cells: injury is followed by rapid and complete regeneration surgical removal of endometrium by curettage is followed by complete regeneration from the basal germinative layer within short time or destruction of erythrocytes stimulates rapid erythroid hyperplasia in bone marrow which results in complete regeneration of erythropoesis Stable cells-quiescent they are considered to be in G0 phase, may undergo rapid proliferation after appropriate stimuli, they may be recruited back to the cell cycle Healing in tissues with prevailing stable cells: regeneration in tissues with most stable cell is possible but the following conditions must be fulfilled: sufficient amount of viable tissue must remain intact fibrous interstitial network and original basement membranes preserved if complete necrosis involves both parenchyma and interstitium- no regeneration is possible and necrosis heals by scar formation Permanent cells- non-dividing cells have no regenerative capacity Healing in tissues with permanent cells: injury to tissue with permanent cells is always followed by scar formation, no regeneration is possible REPAIR BY SCAR FORMATION scar=mass of collagen that is the final result of the process of organization repair by scar occurs: if resolution fails if the injurious agent continuously causes injury in chronic inflammation if parenchymal necrosis cannot be repaired by regeneration because of prevalence of permanent cells Process of repair by scar formation Preparation removal of the inflammatory exudate Debris is liquefied by lysosomal enzymes derived of neutrophil leukocytes is removed by lymphatics, residual particle are phagocytosed by macrophages Ingrowth of granulation tissue granulation tissue is highly vascularized connective tissue composed of newly formed capillaries, proliferating fibroblasts and myofibroblasts, cell debris and residual inflammatory cells major role of the granulation tissue is to occupy the tissue defects lost by injury Grossly granulation tissue is deeply red (because of numerous capillaries) and soft, with granularity of the surface Collagenization collagens are the major fibrillary extracellular proteins Maturation of the scar collagen content of granulation tissue progressively increases with the time, particularly the amount of type I collagen increases the scar becomes less cellular and less vascular the mature scar is composed of hypovascular poorly cellular collagenous mass- composed mostly of collagen type I Contraction and strengthening contraction decreases the size of scar- allows optimal function of the remaining tissue HEALING OF SKIN WOUNDS Healing by first intention (primary union) healing of clean uninfected surgical incision joined by surgical sutures limited number of dead cells, minor discontinuity of basement membrane the incisional space immediately fills with clotted blood containing fibrin Healing by second intention (secondary union) differs from primary healing in several aspects: large tissue defects, such as large infarctions, ulcerations, abscesses large wounds- have always more fibrin in exudate, thus more intense inflammatory reaction much greater amount of granulation tissue is formed final scar is much smaller than original wound due to wound contraction (mostly results of activities of myofibroblasts) - tissue retraction PATHOLOGIC ASPECTS OF REPAIR The factors that modify the quality of tissue repair include: nutrition deficiency, particularly vitamin C deficiency decreases the ability to heal wounds glucocorticoids have anti-inflammatory effect persistent infection is the most important cause of delayed healing mechanical factors, as wound dehiscence low blood supply, presence of foreign bodies disorders of lymphatic flow may slow down the removal of necrotic cells and cause delayed healing the presence or absence of diabetes mellitus and other underlying diseases adequate levels of circulating white blood cells type of injured tissue perfect repair may occur only in tissues built up of labile and stable cells, while injuries to permanent cells results in scarring, such case is myocardial infarction (no regeneration of specialised heart muscle elements) large amounts of exudate slows down a healing healing of exudate include: digestion of the exudate initiated by proteolytic enzymes of leukocytes-resorption of dissolved exudate= process called „ resolution“ the presence of extensive necrosis or large amounts of fibrin in the exudate or low blood and lymphatic rate the process of resolution cannot occur and the exudate is replaced by granulation tissue and transformed into fibrous tissue -organization of exudate for example lung carnification in pathologic healing of pneumonia aberration of growth -hyperplastic scarring- if excessive amounts of collagen accumulate within the scar= keloid -keloid formation appears to an individual predisposition of unknown reasons or excessive formation of granulation tissue= exuberant granulation - granulation tissue protrudes over the surface of the wound and in fact blocks the reepithelization- granulation tissue must be removed surgically